How Do Anti-SARS-CoV-2 mRNA Vaccines Protect from Severe Disease?

COVID-19 pathogenesis develops in two phases. First, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 spreads within the epithelial cells of the mucosa of upper and, possibly, lower respiratory tracts. While the virus dissemination can be controlled by an emerging adaptive host immune response, if the virus diffuses to the pulmonary alveoli, a potentially lethal mechanism can arise in the second phase. It consists of an uncontrolled burst of cytokines/inflammatory factors (i.e., cytokine storm), leading to the insurgence of respiratory symptoms and, consequently, multi-organ failures. Messenger (m)RNA-based vaccines represent the most innovative approach in terms of prophylaxis against SARS-CoV-2-induced disease. The cumulating data indicate that the response to mRNA vaccines is basically ineffective to counteract the viral replication in the upper respiratory tracts, while showing efficacy in containing the development of severe disease. Considering that the antiviral immunity elicited by intramuscularly delivered mRNA vaccines is expected to show similar quantitative and qualitative features in upper and lower respiratory tracts, the different outcomes appear surprising and deserve accurate consideration. In this review, a still unexplored mechanism accounting for the mRNA vaccine effect against severe disease is proposed. Based on well-established experimental evidence, a possible inhibitory effect on alveolar macrophages as a consequence of the diffusion of the extracellular and/or cell-associated Spike protein can be envisioned as a key event counteracting the cytokine storm. This benefit, however, may be associated with defects in the immune functions of macrophages in other tissues whose possible consequences deserve careful evaluation.